WO2012111790A1 - Potentialisateur de l'activité antitumorale d'un agent chimiothérapique - Google Patents

Potentialisateur de l'activité antitumorale d'un agent chimiothérapique Download PDF

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WO2012111790A1
WO2012111790A1 PCT/JP2012/053757 JP2012053757W WO2012111790A1 WO 2012111790 A1 WO2012111790 A1 WO 2012111790A1 JP 2012053757 W JP2012053757 W JP 2012053757W WO 2012111790 A1 WO2012111790 A1 WO 2012111790A1
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cancer
salt
stem cells
agent
valine
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PCT/JP2012/053757
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English (en)
Japanese (ja)
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しのぶ 西谷
博久 矢野
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味の素株式会社
学校法人久留米大学
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Priority to KR1020137024210A priority Critical patent/KR101919747B1/ko
Priority to JP2012558030A priority patent/JP6090836B2/ja
Priority to CN201280009217.8A priority patent/CN103347511B/zh
Priority to EP12747713.1A priority patent/EP2676664B1/fr
Publication of WO2012111790A1 publication Critical patent/WO2012111790A1/fr
Priority to US13/965,844 priority patent/US20130324541A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to an agent for enhancing the antitumor activity of a chemotherapeutic agent against cancer containing cancer stem cells, comprising a branched chain amino acid, an agent for inducing differentiation of cancer stem cells, comprising a branched chain amino acid,
  • the present invention relates to a cancer metastasis / recurrence inhibitory or therapeutic agent containing cancer stem cells in combination with a chemotherapeutic agent.
  • Cancer stem cells are one of the subpopulations of cancer cells contained in tumors, have self-replication and pluripotency, and have the ability to induce cancer when orthotopic transfer is performed. (Non-Patent Document 1).
  • Non-patent Document 2 EpCAM, AFP, and the like are known as markers for liver cancer stem cells (Non-patent Document 2).
  • CD44, CD24, etc. are known as markers for colon cancer stem cells (Non-patent Document 3).
  • markers for breast cancer stem cells CD44, CD24, EpCAM and the like are known (Non-patent Document 1).
  • Cancer stem cells are generally resistant to chemotherapeutic agents because of their slow growth.
  • differentiated cancer cells cancer non-stem cells
  • Many chemotherapeutic agents target the cancer cell growth mechanism, so treatment with chemotherapeutic agents targets only cancer non-stem cells and may not be able to kill the cancer stem cells effectively. Therefore, even if most cancer cells are regressed by treatment with chemotherapeutic agents, if there are only a few cancer stem cells, recurrence can occur, and this is often the cause of metastasis and recurrence in cancer It is considered. Therefore, if the differentiation of cancer stem cells into cancer non-stem cells can be promoted and the sensitivity to chemotherapeutic agents can be increased, it is expected that the entire cancer including cancer stem cells can be efficiently treated or prevented.
  • Branched chain amino acids have been reported to suppress the occurrence and progression of liver cancer so far (Patent Documents 1 to 4). Furthermore, it has been reported that long-term administration of branched-chain amino acids suppresses recurrence of hepatocellular carcinoma (Non-patent Document 4). In addition, it has been reported that branched chain amino acids suppress the activation of Akt, thereby suppressing the development and progression of cancer in patients who are hyperinsulinemia or at risk for hyperinsulinemia ( Patent Document 5). In addition, it has been reported that branched chain amino acids enhance the anti-hepatitis C virus activity of IFN agonists (Patent Document 6).
  • the present invention has developed a technique for promoting the differentiation of cancer stem cells into non-cancer stem cells and increasing the sensitivity to chemotherapeutic agents. Based on this, the present invention effectively treats cancers containing cancer stem cells and prevents cancer recurrence. It is to provide a means to prevent.
  • the present invention is as follows.
  • An agent for enhancing the antitumor activity of a chemotherapeutic agent against cancer including cancer stem cells comprising at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof.
  • the agent according to [1] which is administered in combination with a chemotherapeutic agent to a mammal suffering from cancer including cancer stem cells or a mammal having a history of cancer suffering including cancer stem cells.
  • the agent according to [1] comprising isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof.
  • chemotherapeutic agent is an antimetabolite, an alkylating agent, an anticancer antibiotic, a plant alkaloid, or a molecular target therapeutic agent.
  • chemotherapeutic agent is 5FU.
  • the cancer containing cancer stem cells is a cancer resistant to a chemotherapeutic agent.
  • the cancer containing cancer stem cells is gastric cancer, liver cancer, breast cancer or colon cancer.
  • An agent for treating cancer including cancer stem cells, comprising a combination of at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof and a chemotherapeutic agent.
  • the agent according to [8] comprising isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof.
  • the chemotherapeutic agent is an antimetabolite, an alkylating agent, an anticancer antibiotic, a plant alkaloid, or a molecular target therapeutic agent.
  • the chemotherapeutic agent is 5FU.
  • the agent according to [8], wherein the cancer containing cancer stem cells is a chemotherapy-resistant cancer.
  • the agent according to [8], wherein the cancer containing cancer stem cells is gastric cancer, liver cancer, breast cancer or colon cancer.
  • An agent for preventing metastasis or recurrence of cancer including cancer stem cells comprising a combination of at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof and a chemotherapeutic agent.
  • the agent according to [14] comprising isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof.
  • chemotherapeutic agent is an antimetabolite, an alkylating agent, an anticancer antibiotic, a plant alkaloid, or a molecular target therapeutic agent.
  • the chemotherapeutic agent is 5FU.
  • the agent according to [14], wherein the cancer containing cancer stem cells is a chemotherapy-resistant cancer.
  • the cancer containing cancer stem cells is gastric cancer, liver cancer, breast cancer or colon cancer.
  • An agent for inducing differentiation of cancer stem cells comprising at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof.
  • the agent according to [20], wherein the cancer stem cells are gastric cancer stem cells, liver cancer stem cells, or colon cancer stem cells.
  • cancer containing cancer stem cells is gastric cancer, liver cancer, breast cancer or colon cancer.
  • a combination comprising at least one branched-chain amino acid selected from isoleucine, leucine and valine or a salt thereof, and a chemotherapeutic agent for use in the treatment of cancer including cancer stem cells.
  • a combination comprising at least one branched-chain amino acid selected from isoleucine, leucine and valine, or a salt thereof, and a chemotherapeutic agent for use in preventing metastasis or recurrence of cancer containing cancer stem cells.
  • a method for enhancing antitumor activity of a chemotherapeutic agent in a mammal comprising administering an effective amount of at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof to the mammal.
  • a method for treating cancer including cancer stem cells in a mammal comprising administering an effective amount of at least one branched chain amino acid selected from isoleucine, leucine and valine, or a salt thereof, and a chemotherapeutic agent to the mammal.
  • Metastasis of cancer containing cancer stem cells in the mammal comprising administering to the mammal an effective amount of at least one branched chain amino acid selected from isoleucine, leucine and valine, and a salt thereof, and a chemotherapeutic agent How to prevent recurrence.
  • a method for inducing differentiation of cancer stem cells in a mammal comprising administering to the mammal an effective amount of at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof.
  • a method for suppressing metastasis of cancer including cancer stem cells in a mammal comprising administering to the mammal an effective amount of at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof.
  • Branched-chain amino acids promote the differentiation of cancer stem cells into cancer non-stem cells and increase sensitivity to chemotherapeutic agents, so they are combined with chemotherapeutic agents and administered to patients with cancers that contain cancer stem cells By doing so, it is possible to treat cancer effectively.
  • metastasis and recurrence of cancer can be effectively prevented by administering a branched chain amino acid in combination with a chemotherapeutic agent to a patient with a history of cancer including cancer stem cells.
  • Figure 3 shows the effect of BCAA on EpCAM1, AFP and CYP3A4 mRNA expression in HAK4 cells.
  • shaft shows the relative mRNA expression level of each gene when the expression at the time of LC2.5% processing is set to 1.
  • T-test, n 6, * p ⁇ 0.05, average value + SE.
  • the apoptosis induction of HAK4 cell by combined use of 5FU and BCAA is shown.
  • the vertical axis shows the percentage of Annexin V positive cells.
  • T-test, n 7, * p ⁇ 0.05, average value + SE.
  • FIG. 5 shows the effect of BCAA on EpCAM1, AFP and CYP3A4 mRNA expression in HAK1B cells.
  • shaft shows the relative mRNA expression level of each gene when the expression at the time of LC2.5% processing is set to 1.
  • T-test, n 6, * p ⁇ 0.05, average value + SE.
  • the time-dependent change of the tumor volume in a Balb / c nude mouse transplanted with HAK1B cells is shown.
  • Group 1 vehicle + casein mixed diet (control group), group 2: 5FU + casein mixed diet, group 3: vehicle + BCAA mixed diet, group 4: 5FU + BCAA mixed diet.
  • Tumor volume at day 15 is shown.
  • Dunnet test, n 6, * p ⁇ 0.05, *** p ⁇ 0.001, mean + SE. Tumor weight on day 15 is shown.
  • Figure 3 shows the effect of BCAA on CD44 expression in HCT116 cells.
  • the vertical axis shows the percentage of CD44 positive cells.
  • T-test, n 7, * p ⁇ 0.05, average value + SE.
  • the apoptosis induction of HCT116 cell by combined use of 5FU and BCAA is shown.
  • the vertical axis shows the percentage of Annexin V positive cells.
  • T-test, n 14, * p ⁇ 0.05, average value + SE.
  • Figure 3 shows the effect of BCAA on liver metastasis of HCT116 cells.
  • the vertical axis represents the number of liver metastases per mouse.
  • the cell death induction of MKN45 cells by the combined use of 5FU and BCAA is shown.
  • shaft shows the relative value of OD450nm.
  • T-test, * p ⁇ 0.05, n 8.
  • the apoptosis induction of MKN45 cells by the combined use of 5FU and BCAA is shown.
  • the vertical axis shows the percentage of apoptotic cells.
  • T-test, * p ⁇ 0.05, n 8.
  • Figure 3 shows the effect of BCAA on CD44 expression in MKN45 cells.
  • the vertical axis shows the percentage of CD44 positive cells.
  • T-test, * p ⁇ 0.01, n 8. Tumor volume after 6 weeks is shown.
  • Dunnet test, n 6, ** p ⁇ 0.01, mean + SE.
  • FIG. 1 The growth suppression of MDA-MB231 cell by combined use of 5FU and BCAA is shown.
  • Figure 3 shows the effect of BCAA on CD44 expression in MDA-MB231 cells. The vertical axis shows the percentage of CD44 positive cells. Student test vs RPMI-10%, average + SE.
  • the present invention relates to a cancer comprising cancer stem cells, comprising at least one branched chain amino acid selected from isoleucine, leucine and valine, or a salt thereof (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof).
  • An agent (or composition) for enhancing the antitumor activity of a chemotherapeutic agent and / or an agent (or composition) for inducing differentiation of cancer stem cells hereinafter, these preparations are referred to as the agent or composition of the present invention) (Also referred to as a thing).
  • the agent (or composition) of the present invention may be an agent (or composition) for suppressing metastasis of cancer containing cancer stem cells.
  • the agent or composition of the present invention comprises at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof (preferably a combination comprising isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof).
  • the present invention has been completed based on the finding that the differentiation of cancer stem cells into cancer non-stem cells is promoted and the antitumor activity of a chemotherapeutic agent against cancer containing cancer stem cells is enhanced by this effect.
  • cancer stem cells are resistant to chemotherapeutic agents because of their slow growth.
  • differentiated cancer cells are generally sensitive to chemotherapeutic agents because of their high growth speed.
  • At least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof is applied to cancer including cancer stem cells.
  • the sensitivity of the cancer to the chemotherapeutic agent is increased, and as a result, the antitumor activity of the chemotherapeutic agent against the cancer is enhanced.
  • the agent or composition of the present invention comprises at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof. And the combination) was completed based on the finding that cancer stem cells were differentiated into cancer non-stem cells and this effect suppressed the metastatic potential of cancers containing cancer stem cells.
  • cancer stem cells have self-renewal ability and pluripotency, and have a tumor-initiating ability when orthotopic transfer is performed (the tumor formed here is A cancer cell that is a phenocopy of the tumor from which the cancer stem cell is derived (Nat Rev Cancer, vol.5, pages 425-436, 2006)
  • the presence of markers that are specifically expressed in cancer stem cells is known. Based on the expression of these markers, whether cancer cells are cancer stem cells or cancer stem cells are included in cancer. Can be evaluated.
  • the liver cancer stem cell is EpCAM + AFP + (Cancer Research, vol. 65, No. 8, pages 1451-1461, 2008).
  • the colon cancer stem cells are CD44 + CD24 + (PNAS, vol. 171, No. 8, pages 3722-3727, 2010).
  • the breast cancer stem cells are CD44 + CD24 low + EpCAM + (PNAS, vol. 100, No. 7, pages 3982-3988, 2003).
  • the pancreatic cancer stem cell is CD44 + .
  • the expression of these markers is evaluated by flow cytometry or immunohistological staining using specific antibodies against these marker proteins, and when specific staining is observed by at least one of the methods.
  • the marker expression is positive (+).
  • Specific antibodies against these marker proteins useful for flow cytometry or immunohistological staining are widely available on the market. Those skilled in the art can easily determine whether cancer cells are cancer stem cells using these antibodies. Or whether the cancer contains cancer stem cells.
  • the gastric cancer stem cell is CD44 + .
  • differentiation of cancer stem cells into non-stem cancer cells can be evaluated using the decrease in marker expression of these cancer stem cells as an index.
  • the expression of a cancer stem cell marker in cancer is reduced after the treatment as compared with that before the treatment under specific conditions, it can be said that the treatment induces differentiation of cancer stem cells into non-cancer stem cells.
  • the ratio of the number of cells expressing the cancer stem cell marker protein in the whole cancer cells or the amount of the cancer stem cell marker protein in the whole cancer decreases, the expression of the cancer stem cell marker decreases. It is judged that
  • cancer includes cancer derived from any tissue.
  • examples of cancer include liver cancer, colon cancer, kidney cancer, melanoma, pancreatic cancer, thyroid cancer, stomach cancer, lung cancer (small cell lung cancer, non-small cell lung cancer), brain tumor, uterine cancer, breast cancer, multiple osteosarcoma, ovarian cancer.
  • the cancer containing cancer stem cells to which the agent of the present invention is applied is resistant to a chemotherapeutic agent.
  • “Chemotherapeutic agent resistance” refers to the property of not exhibiting a significantly detectable response upon administration of the highest dose of chemotherapeutic agent approved for human application.
  • cancer stem cells are resistant to chemotherapeutic agents because of their slow growth speed, and therefore, cancers that are resistant to chemotherapeutic agents may contain many cancer stem cells. is there. Therefore, by applying the agent or composition of the present invention to a cancer resistant to a specific chemotherapeutic agent, differentiation from cancer stem cells to cancer non-stem cells is promoted, and the cancer is treated against the chemotherapeutic agent. High sensitivity is expected.
  • liver cancer, colon cancer, kidney cancer, melanoma, pancreatic cancer, thyroid cancer, gastric cancer, lung cancer, breast cancer and non-small cell lung cancer are generally less sensitive to chemotherapeutic agents, and chemotherapeutic agents are effective. It is known to be difficult. Therefore, by applying the agent or composition of the present invention to these cancers (preferably stomach cancer, liver cancer, breast cancer or colon cancer) and promoting the differentiation of cancer stem cells contained in these cancers, Expected to be more sensitive to therapeutic agents.
  • a chemotherapeutic agent refers to a compound that acts directly on cancer cells, suppresses its division, and has the ability to kill.
  • chemotherapeutic agents include antimetabolites, platinum preparations, alkylating agents, anticancer antibiotics, plant alkaloids, molecular targeted therapeutic agents, and the like.
  • an antimetabolite is a substance that has a chemical structure similar to that of a nucleic acid material when cancer cells divide and proliferate, thereby preventing DNA synthesis and inhibiting cancer cell metabolism.
  • Antimetabolites include pyrimidine antimetabolites such as 5-fluorouracil (5FU), tegafur, carmofur, doxyfluridine, broxuridine, cytarabine, enocitabine, hydroxyfuridine, hydroxycarbamide, methotrexate, fludarabine phosphate; 6-mercaptopurine And purine metabolism antagonists such as 6-thioguanine, thioinosine, and gemcitabine hydrochloride.
  • the antimetabolite is preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur.
  • Platinum preparations are the bases of DNA, guanine and adenine that bind to the N-7 position at two chlorine atom sites, form crosslinks in the DNA strand, and inhibit DNA synthesis to proliferate cancer cells. It refers to a chemotherapeutic agent that exerts an effect of suppressing the above. Examples of the platinum preparation include cisplatin, carboplatin, nedaplatin, oxaliplatin and the like.
  • alkylating agent refers to a chemotherapeutic agent that exerts an effect of inhibiting the growth of cancer cells by cleaving by alkylating DNA.
  • alkylating agents include nitrogen mustard, nitrogen mustard N-oxide, chlorambucil and other nitrogen mustard alkylating agents; ethyleneimine derivatives such as carbocone and thiotepa; sulfonic acid esters such as busulfan and toproic acid toprosulphane Nitrosourea derivatives such as nimustine hydrochloride and the like.
  • Anticancer antibiotics include mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin, epirubicin and other anthracycline antibiotic antitumor agents; chromomycin A 3 , Actinomycin D and the like.
  • Plant alkaloids include vinca alkaloids such as vinblastine, vincristine and vindesine; epipodophyllotoxins such as etoposide and teniposide; taxane alkaloids such as paclitaxel and dotaxel.
  • the molecular target therapeutic agent refers to a compound having an activity of killing cancer cells by targeting a molecule involved in cancer cell proliferation and inhibiting the molecule.
  • molecular targeted therapeutic agents include imatinib, gefitinib, erlotinib, vandetanib, sunitinib, sorafenib, rituximab, cetuximab, infliximab, trastuzumab, bevacizumab and the like.
  • the agent or composition of the present invention enhances the antitumor activity of an antimetabolite (preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur) against liver cancer including liver cancer stem cells. belongs to.
  • an antimetabolite preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur
  • the agent or composition of the present invention enhances the antitumor activity of an antimetabolite (preferably pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur) against colorectal cancer including colorectal cancer stem cells. belongs to.
  • an antimetabolite preferably pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur
  • the agent or composition of the present invention comprises gastric cancer comprising gastric cancer stem cells, colon cancer comprising colon cancer stem cells, cervical cancer comprising cervical cancer stem cells, endometrial cancer comprising endometrial cancer stem cells, digestive organ cancer Antimetabolite (preferably pyrimidine antimetabolite, preferably pyrimidine antimetabolite, for pancreatic cancer including stem cells, pancreatic cancer including pancreatic cancer stem cells, rectal cancer including rectal cancer stem cells, breast cancer including breast cancer stem cells, or ovarian cancer including ovarian cancer stem cells Is for enhancing the antitumor activity of 5-fluorouracil or tegafur).
  • gastric cancer comprising gastric cancer stem cells
  • colon cancer comprising colon cancer stem cells
  • cervical cancer comprising cervical cancer stem cells
  • endometrial cancer comprising endometrial cancer stem cells
  • digestive organ cancer Antimetabolite preferably pyrimidine antimetabolite, preferably pyrimidine antimetabolite, for pancreatic cancer including stem cells, pancreatic cancer including pancreatic cancer
  • Isoleucine, leucine, and valine which are active ingredients (branched chain amino acids) in the agent or composition of the present invention, can be used in any of L-form, D-form, and DL-form, but preferably L-form, DL-form, more preferably L-form.
  • Isoleucine, leucine and valine can be used not only in free form but also in salt form.
  • the salt form include acid addition salts and base addition salts, but any form can be adopted as long as it is a chemically acceptable salt.
  • the salt form is preferably a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include salts with acids and salts with bases.
  • acids that are added to isoleucine, leucine, or valine to form pharmaceutically acceptable salts include inorganic acids such as hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, Organic acids such as tartaric acid, maleic acid, fumaric acid or monomethyl sulfuric acid can be mentioned.
  • bases that form pharmaceutically acceptable salts by adding to isoleucine, leucine, or valine, respectively include metal hydroxides such as sodium and potassium, metal carbonates such as calcium, and inorganic such as ammonia. Examples include bases, organic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine.
  • the agent or composition of the present invention may contain at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof, and the following embodiments are included in the present invention: An embodiment containing only isoleucine or a salt thereof as a branched chain amino acid; An embodiment containing only leucine or a salt thereof as a branched chain amino acid; An embodiment containing only valine or a salt thereof as a branched chain amino acid; An embodiment containing isoleucine or a salt thereof and leucine or a salt thereof as a branched chain amino acid; An embodiment containing isoleucine or a salt thereof and valine or a salt thereof as a branched chain amino acid; An embodiment containing leucine or a salt thereof and valine or a salt thereof as a branched chain amino acid; An embodiment containing leucine or a salt thereof and valine or a salt thereof as a branched chain amino acid; and an embodiment containing isole
  • a person skilled in the art can determine the compounding ratio (weight ratio) of the branched chain amino acids contained in the agent or composition of the present invention. Can be adjusted as appropriate within a range having an activity to enhance the antitumor activity of a chemotherapeutic agent against cancer including stem cells.
  • isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof are added.
  • the blending ratio of these three amino acids is usually 1: 1 to 3: 0.5 to 2.0, preferably 1: 1. 5 to 2.5: 0.8 to 1.5, more preferably 1: 1.9 to 2.2: 1.1 to 1.3, and most preferably 1: 2: 1.2. is there.
  • the agent of the present invention contains an isoleucine salt, a leucine salt, or a valine salt
  • the calculation of the weight ratio should be carried out after all the branched chain amino acid salts are converted to free form. To do.
  • the agent and composition of the present invention can be administered to animals (preferably, mammals such as humans).
  • the dosage form / dosage form may be either oral or parenteral, and oral dosage forms include solids such as powders, granules, capsules, tablets, chewables, and solutions. And liquids such as syrups, and parenteral agents include injections, infusions, nasal / pulmonary sprays, and the like.
  • the agent or composition of the present invention can be formulated into pharmaceuticals of these dosage forms by a conventional method.
  • the branched chain amino acid is preferably administered orally to the subject.
  • branched chain amino acids can be administered intravenously / arterially as amino acid infusions.
  • the agent of the present invention can be prepared by using an appropriate pharmaceutically acceptable carrier such as an excipient, a binder, a lubricant, a solvent, a disintegrant, a solubilizing agent, a suspension, as required in the preparation. It is formulated by blending agents, emulsifiers, isotonic agents, stabilizers, soothing agents, preservatives, antioxidants, flavoring agents, coloring agents and the like. Furthermore, the composition of this invention can be prepared with the said support
  • excipients examples include sugars such as lactose, glucose, D-mannitol, organic excipients such as starches and celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin.
  • a lubricant pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.
  • fatty acid salts such as stearic acid and stearate, talc, silicates, etc., purified water, physiological saline, etc.
  • Cellulose and starch, etc. used as a solubilizer include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and the like.
  • a tonicity agent sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium and the like, polysorbates, polyoxyethylene hydrogenated castor oil, etc.
  • Sodium chloride, potassium chloride, sugars, glycerin, urea, etc., and stabilizers such as polyethylene glycol, sodium dextran sulfate, and other amino acids.
  • a soothing agent glucose, calcium gluconate, procaine hydrochloride, etc., and as preservatives, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are antioxidants.
  • As the agent sulfite, ascorbic acid and the like are used.
  • sweeteners, flavors and the like normally used in the pharmaceutical and food fields are used, and as the coloring agent, they are usually used in the pharmaceutical and food fields. Coloring agents can be mentioned.
  • the agent or composition of the present invention can be provided as a food or drink.
  • a food or drink there is no particular difficulty.
  • a branched chain amino acid preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof
  • the obtained food or drink can be provided as a health functional food.
  • Functional health foods contain health functional ingredients that affect the body's physiological functions and biological activities, and are taken for specific health purposes in the diet. Expected food.
  • Health functional foods are sometimes called functional foods and health foods (including nutritional supplements).
  • Functional foods are foods made by making use of the functions of bioregulatory components contained in foods, and health foods generally refer to food groups that are considered to be useful for health promotion. These include nutritional supplements based on specific nutrients.
  • Functional health foods include foods for specified health use and nutritional functional foods, who are receiving chemotherapeutic agents, who have cancer with cancer stem cells, or who have a history of cancer with cancer stem cells By feeding as a daily dietary supplement in a patient, the sensitivity of the cancer to the chemotherapeutic agent can be increased.
  • Such a health functional food can be labeled as being used for enhancing the antitumor activity of a chemotherapeutic agent against cancer including cancer stem cells.
  • the content of the branched chain amino acid (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof) contained in the agent or composition of the present invention varies depending on the form of the preparation, etc. It is usually 1 to 100% by weight, preferably 10 to 100% by weight, more preferably 30 to 100% by weight, still more preferably 50 to 100% by weight based on the whole.
  • Preferred examples of the agent and composition of the present invention include isoleucine, leucine and valine in a weight ratio of 1: 2: 1.2 (isoleucine: 0.952 g, leucine: 1.904 g, valine: 1.144 g).
  • the branched chain amino acid preparation Rebact (registered trademark) granules (Ajinomoto Co., Inc.) (orally administered) can be mentioned.
  • Suitable parenteral administration agents include aminic high-concentration amino acid infusions ((registered trademark) intravenous infusion (Ajinomoto Pharmaceutical Co., Ltd.)) and morihepamine ((registered trademark) intravenous infusion (Ajinomoto Pharmaceutical Co., Ltd.)). Can be mentioned.
  • the dose of the agent or composition of the present invention varies depending on the age / weight / pathology of the subject patient, administration method, etc., but in an embodiment containing isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof.
  • the standard daily dose is 0.5 to 30.0 g of isoleucine, 1.0 to 60.0 g of leucine, and 0.5 to 30.0 g of valine.
  • Administration is divided into 6 times, preferably 1 to 3 times.
  • the agent or composition of the present invention contains a branched-chain amino acid salt, the dose is calculated after all the branched-chain amino acid salts are converted to free form.
  • the dosage (intake amount) of the branched chain amino acid which is the active ingredient used in the present invention
  • the above-mentioned active ingredient of the drug used for the purpose of treatment, prevention or the like of the disease targeted by the present invention Since the calculation range has been determined, branched chain amino acids that are ingested or administered for other purposes, such as for the need of a normal diet or for the treatment of other diseases, are included in the calculation. There is no need. For example, it is not necessary to calculate by subtracting the amount of branched chain amino acids per day taken from a normal diet from the daily dose of the active ingredient in the present invention.
  • the agent of the present invention is an embodiment containing two or three branched chain amino acids selected from isoleucine, leucine and valine or a salt thereof, isoleucine, leucine and valine or a salt thereof which is an active ingredient of the present invention,
  • Each may be contained alone or in any combination in the preparation, or all may be contained in one preparation.
  • their administration route and dosage form may be the same or different, and the timing of administration of each may be the same or different. It is determined as appropriate depending on the type and effect of the drug used in combination. That is, the agent of the present invention may be a preparation containing a plurality of branched chain amino acids or salts thereof simultaneously, or may be a combination agent that is separately formulated and used together.
  • weight ratio indicates the ratio of the weight of each amino acid component in the agent and composition of the present invention.
  • each active ingredient of isoleucine, leucine and valine is included in one preparation, it is a ratio of individual contents, and each active ingredient is included in a plurality of preparations alone or in any combination In some cases, it is the ratio of the weight of each active ingredient included in each formulation.
  • the actual dose ratio is a ratio of a single dose or a daily dose of each active ingredient per administration subject (ie, patient).
  • the weight ratio corresponds to the dose ratio.
  • the ratio of the total amount of each active ingredient in each preparation administered once or daily corresponds to the weight ratio.
  • Isoleucine, leucine, and valine have already been widely used in the pharmaceutical and food fields, and safety has been established.
  • the present invention contains these branched chain amino acids in a ratio of 1: 2: 1.2.
  • the acute toxicity (LD50) in these agents and compositions is 10 g / Kg or more in the oral administration of mice.
  • At least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof is a cancer of cancer stem cells. It promotes differentiation into non-stem cells, and this effect enhances the antitumor activity of chemotherapeutic agents against cancers containing cancer stem cells. Accordingly, in one embodiment, the agent or composition of the present invention is administered to a mammal (eg, human) suffering from cancer comprising cancer stem cells.
  • At least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or
  • a mammal eg, human
  • At least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or
  • the agent or composition of the present invention is administered to a mammal (eg, human) having a history of cancer including cancer stem cells.
  • Cancer stem cells generally have slow cell proliferation and are resistant to chemotherapeutic agents. Once cancers containing cancer stem cells have developed, the results of treatment with chemotherapeutic agents, etc., are apparently in remission, Even when the symptoms of cancer disappear, cancer stem cells remain in the body, which is considered to cause cancer metastasis and recurrence.
  • recurrence of cancer is meant that after treatment has completely or partially ameliorated the symptoms of cancer, the cancer cells proliferate again and the symptoms of cancer reappear or worsen.
  • the agent or composition of the present invention when administered to a mammal (eg, human) having a history of cancer including cancer stem cells, it may remain in the mammal body. Promotes differentiation of cancer stem cells into non-cancer stem cells and enhances sensitivity to chemotherapeutic agents.
  • the agent or composition of the present invention is administered to a mammal in combination with a chemotherapeutic agent.
  • a mammal suffering from cancer containing cancer stem cells in combination with a chemotherapeutic agent the cancer can be efficiently treated.
  • metastasis or recurrence of the cancer can be efficiently prevented. it can.
  • the present invention provides at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof) (hereinafter these are simply branched chains).
  • An agent (or composition) for treating cancer containing cancer stem cells and / or cancer metastasis or recurrence containing cancer stem cells, which is a combination of a chemotherapeutic agent and an amino acid) (Hereinafter, these preparations are also referred to as the preventive or therapeutic agent of the present invention).
  • the cancer to which the preventive or therapeutic agent of the present invention can be applied is the same as the cancer to which the agent or composition of the present invention can be applied.
  • the cancer comprising cancer stem cells to which the agent of the present invention is applied is chemotherapeutic drug resistant.
  • liver cancer, colon cancer, kidney cancer, melanoma, pancreatic cancer, thyroid cancer, gastric cancer, lung cancer, breast cancer and non-small cell lung cancer are generally less sensitive to chemotherapeutic agents and chemotherapeutic agents are less effective It has been known. Therefore, when the preventive or therapeutic agent of the present invention is applied to these cancers (preferably stomach cancer, liver cancer, breast cancer or colon cancer), branched chain amino acids (preferably isoleucine or a salt thereof) contained in the preventive or therapeutic agent of the present invention.
  • these cancers preferably stomach cancer, liver cancer, breast cancer or colon cancer
  • branched chain amino acids preferably isoleucine or a salt thereof
  • Leucine or a salt thereof, and valine or a salt thereof promote the differentiation of cancer stem cells contained in cancer and become more sensitive to chemotherapeutic agents of these cancers, and are included in the preventive or therapeutic agent of the present invention As a result, effective killing of cancer stem cells is expected.
  • the prophylactic or therapeutic agent of the present invention comprises an antimetabolite (preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur) as a chemotherapeutic agent to prevent or prevent liver cancer including liver cancer stem cells. It is for treatment.
  • an antimetabolite preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur
  • the prophylactic or therapeutic agent of the present invention comprises an antimetabolite (preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur) as a chemotherapeutic agent to prevent or prevent colon cancer including colon cancer stem cells. It is for treatment.
  • an antimetabolite preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur
  • the preventive or therapeutic agent of the present invention comprises an antimetabolite (preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur) as a chemotherapeutic agent, and prevents or treats gastric cancer containing gastric cancer stem cells. Is to do.
  • an antimetabolite preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur
  • the preventive or therapeutic agent of the present invention comprises an antimetabolite (preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur) as a chemotherapeutic agent, and gastric cancer, colon cancer stem cells including gastric cancer stem cells.
  • an antimetabolite preferably a pyrimidine antimetabolite, more preferably 5-fluorouracil or tegafur
  • gastric cancer colon cancer stem cells including gastric cancer stem cells.
  • colon cancer cervical cancer including cervical cancer stem cells, endometrial cancer including endometrial cancer stem cells, digestive organ cancer including digestive organ cancer stem cells, pancreatic cancer including pancreatic cancer stem cells, rectal cancer including rectal cancer stem cells, breast cancer stem cells Breast cancer containing ovarian cancer or ovarian cancer containing ovarian cancer stem cells.
  • the administration time of the branched chain amino acid and the chemotherapeutic agent is not limited, and the branched chain amino acid and the chemotherapeutic agent may be administered simultaneously to the administration subject, Administration may be performed with a time difference.
  • the dosage of the branched chain amino acid and the chemotherapeutic agent is particularly limited as long as the intended effect (effect of treating cancer including cancer stem cells, effect of preventing metastasis or recurrence of cancer including cancer stem cells) can be achieved. It can be appropriately selected depending on the administration subject, administration route, symptom, combination and the like.
  • the branched chain amino acid is preferably administered in an amount that promotes differentiation of cancer stem cells into non-cancer stem cells, and the chemotherapeutic agent is administered in an amount that kills the cancer non-stem cells.
  • the administration mode of the branched chain amino acid and the chemotherapeutic agent is not particularly limited, and it is sufficient that the branched chain amino acid and the chemotherapeutic agent are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating a branched chain amino acid and a chemotherapeutic agent, and (2) separate preparation of the branched chain amino acid and the chemotherapeutic agent.
  • the administration form and dosage form of the preventive or therapeutic agent of the present invention may be either oral administration or parenteral administration.
  • oral administration agent include solid agents such as powders, granules, capsules, tablets, chewable agents, and solutions.
  • liquids such as syrups, and parenteral agents include injections, infusions, nasal and pulmonary sprays, and the like.
  • agent or composition of the present invention can be formulated into pharmaceuticals of these dosage forms by a conventional method.
  • the preventive or therapeutic agent of the present invention is an appropriate pharmaceutically acceptable carrier, for example, an excipient, a binder, a lubricant, a solvent, a disintegrant, a solubilizing agent, as necessary in the preparation.
  • an excipient for example, an excipient, a binder, a lubricant, a solvent, a disintegrant, a solubilizing agent, as necessary in the preparation.
  • Suspending agents, emulsifiers, isotonic agents, stabilizers, soothing agents, preservatives, antioxidants, flavoring agents, coloring agents, and the like are examples of the like.
  • the content of the branched-chain amino acid in the preparation containing the branched-chain amino acid is the same as that of the above-described agent or composition of the present invention.
  • the content of the chemotherapeutic agent in the preparation containing the chemotherapeutic agent is used in combination with the branched chain amino acid to treat cancer including cancer stem cells. Or, as long as it can prevent metastasis or recurrence of cancer containing cancer stem cells, although it varies depending on the form of the preparation and the type of chemotherapeutic agent, it is usually about 0.1 to 99.9 for the whole preparation. % By weight, preferably about 1 to 99% by weight, more preferably about 10 to 90% by weight.
  • the content may be the same as described above.
  • the mixing ratio of the branched chain amino acid and the chemotherapeutic agent can be appropriately selected depending on the administration subject, administration route, symptom, type of chemotherapeutic agent, and the like.
  • the dosage of the branched chain amino acid is the same as the dosage of the branched chain amino acid in the agent or composition of the present invention described above, and in an embodiment containing isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof.
  • the standard daily dose is 0.5 to 30.0 g of isoleucine, 1.0 to 60.0 g of leucine, and 0.5 to 30.0 g of valine.
  • Administration is divided into 6 times, preferably 1 to 3 times.
  • the dose of the chemotherapeutic agent is not particularly limited as long as it can treat cancer including cancer stem cells, or prevent metastasis or recurrence of cancer including cancer stem cells, in combination with a branched chain amino acid. It can be set as appropriate depending on the administration route, the type of antitumor agent and the like.
  • the frequency of administration of the branched-chain amino acid and / or chemotherapeutic agent varies depending on the administration subject, symptoms, administration route, type of antitumor agent, etc., for example, once every 1 to 7 days, preferably 1 to 3 days The frequency is once.
  • the frequency of administration of the branched chain amino acid and / or chemotherapeutic agent is usually 1 to 15 times, preferably about 2 to 10 times, although it varies depending on the administration subject, symptoms, administration route, type of antitumor agent, and the like.
  • the preparation containing the branched chain amino acid and the preparation containing the chemotherapeutic agent may be administered at the same time.
  • a preparation containing a therapeutic agent may be administered first, followed by a preparation containing a branched chain amino acid, or a preparation containing a branched chain amino acid may be administered first, followed by a preparation containing a chemotherapeutic agent May be administered.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method.
  • a preparation containing a branched chain amino acid when administered first, a preparation containing a branched chain amino acid was administered. Thereafter, a method of administering a preparation containing a chemotherapeutic agent within 1 minute to 14 days can be mentioned. In the case of administering a preparation containing a chemotherapeutic agent first, a method of administering a preparation containing a branched chain amino acid within 1 minute to 14 days after administration of the chemotherapeutic agent can be mentioned.
  • cancer stem cells are resistant to chemotherapeutic agents because of their slow growth speed.
  • differentiated cancer cells are generally sensitive to chemotherapeutic agents because of their high growth speed.
  • at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof is applied to the cancer stem cell, and cancer of the cancer stem cell.
  • the administration of the chemotherapeutic agent is performed simultaneously with the administration of the above-mentioned branched chain amino acid (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof) or the above-mentioned branched chain amino acid. It is preferable that a certain period after administration of (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof) is preferable.
  • the above-mentioned branched chain amino acid preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof
  • a chemotherapeutic agent preferably administered simultaneously.
  • administering the above-mentioned branched chain amino acid preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof, and then administering a chemotherapeutic agent.
  • the administration protocol of the preventive or therapeutic agent of the present invention preferably, (1) administering the above-mentioned branched chain amino acid (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof) and a chemotherapeutic agent at the same time in single or multiple times, (2)
  • the above-mentioned branched chain amino acid preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof
  • a chemotherapeutic agent is administered as a second step.
  • the above-mentioned branched chain amino acid (preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof) is administered once or a plurality of times as a first step, and the above-mentioned branched chain amino acid is a second step.
  • isoleucine or a salt thereof, leucine or a salt thereof, and valine or a salt thereof and a chemotherapeutic agent are administered one or more times at the same time;
  • the process of repeating the process of (2) or (3) several times is included.
  • the above-mentioned branched chain amino acids preferably isoleucine or a salt thereof, leucine or a salt thereof, and valine or The transfusion containing the salt
  • the above-mentioned branched chain amino acids may be injected into the artery together with the chemotherapeutic agent when hepatic artery injection chemotherapy is performed.
  • interferon may be injected into the artery together with the above infusion agent and chemotherapeutic agent.
  • the interval between the last administration in the first stage and the last administration in the second stage varies depending on the administration subject, symptoms, administration route, type of chemotherapeutic agent, etc., but usually 1 Within minutes to 14 days.
  • the cancer stem cell is transformed into a cancer non-stem cell.
  • the confirmation can be performed by measuring the expression of a cancer stem cell marker by an immunological technique using an antibody that specifically recognizes the marker protein.
  • the expression of a cancer stem cell marker in cancer is decreased after the administration compared to before administration of the above-mentioned branched chain amino acid, it can be said that the administration induced differentiation of cancer stem cells into non-cancer stem cells. .
  • administration of the chemotherapeutic agent which is a 2nd step can be implemented.
  • the agent or composition of the present invention may remain in the body of a mammal by being administered to a mammal (eg, human) having a history of cancer including cancer stem cells.
  • a mammal eg, human
  • a mammal eg, human
  • promotes differentiation of cancer stem cells into cancer non-stem cells promotes the differentiation of cancer stem cells into cancer non-stem cells, suppresses the expression of adhesion molecules involved in cancer metastasis such as CD44, and this effect
  • the metastatic ability of cancer including stem cells is suppressed. Therefore, by administering the agent or composition of the present invention to a mammal having a history of cancer including cancer stem cells, metastasis and recurrence of the cancer can be efficiently prevented without the need for combined use with a chemotherapeutic agent. can do.
  • Example 1 Effect of BCAA on expression of stem cell marker and differentiation marker in human liver cancer cell line HAK4
  • Human liver cancer cell line HAK4 was seeded on a plate at a concentration of 12000 cells / well, and 2 mM BCAA or LC 2.5% medium. Incubated for 72 hours.
  • the BCAA concentration “2 mM” is the sum of the concentrations of all amino acids isoleucine, leucine and valine.
  • the composition of the LC 2.5% medium is shown in the table below. In addition, “2.5%” of LC 2.5% indicates the content of bovine serum.
  • Fischer ’s ratio means Valine® + Leucine® + Isoleucine / Tyrosine® + Phenylalanine.
  • the supernatant was removed and at least 1 ml of 75 (v / v)% ethanol was added to the precipitate, vortexed and centrifuged at 7500 ⁇ g, 4 ° C. for 5 minutes.
  • the total RNA solution was obtained by removing the supernatant, drying the precipitate for a short time, adding distilled water and dissolving.
  • EpCAM Epidermal cell adhesion molecule
  • AFP ⁇ -feto protein
  • CYP3A4 cytochrome P450 3A4; The expression of mRNA of differentiation marker
  • Example 2 Effect of combined use of 5FU (5-fluorouracil) and BCAA on human liver cancer cell line HAK4 (in vitro test) Human liver cancer cell line HAK4 was seeded on a plate at a concentration of 3000 cells / well and cultured for 72 hours under the following conditions: LC 2.5% medium BCAA (2 mM) ⁇ 5FU (2.5 ⁇ g / ml) BCAA (2 mM) + 5FU (2.5 ⁇ g / ml)
  • Array Scan (Thermo Fisher). That is, cells in a 96-well plate were rinsed with 1X Binding Buffer, 40 ⁇ l of 1X Binding Buffer containing annexin V (1 ⁇ l) was added to each well, and incubated at room temperature in the dark for 5 to 15 minutes. Cells were washed and fixed in 2% formaldehyde. After adding 100 ⁇ l of PBS containing Hoechst 33258 solution and incubating for 5 minutes in the dark, apoptotic cells (%) were detected by Array Scan.
  • Example 3 Effect of BCAA on expression of stem cell marker and differentiation marker in human liver cancer cell line HAK1B
  • human liver cancer cell line HAK1B was seeded on a plate at a concentration of 4000 cells / well and 2 mM BCAA.
  • the cells were cultured in LC 2.5% medium for 72 hours.
  • Cells were collected after 72 hours of culture, and total RNA was purified by ISOGEN (Nippon Gene).
  • ISOGEN Natural Gene
  • the expression of EpCAM, AFP and CYP3A4 mRNA was quantified by RT-PCR.
  • BCAA decreased expression of EpCAM and AFP, which are markers of liver cancer stem cells, and increased expression of CYP3A4, which is a differentiation marker, in HAK1B cells as well as HAK4 cells. From the above results, it was suggested that BCAA induces the differentiation of cancer stem cells of liver cancer into cancer non-stem cells and decreases the cancer stem cells.
  • Example 4 Effect of combined use of 5FU (5-fluorouracil) and BCAA on human liver cancer cell line HAK1B (in vivo test) Seven-week-old female BALB / c nude mice (purchased from Nippon Charles River) were subcutaneously transplanted with 7 million HAK1B cells / individual. One week later, grouping was performed based on the tumor area. 5FU 250 ⁇ g / tumor (vehicle 10% DMSO / DW) was administered intratumorally (see Cancer Research, 70 (11), 4687-4697, 2010) and 3 (w / w)% BCAA diet or 3 (w / W) A casein mixed diet was provided for 2 weeks.
  • 5FU 250 ⁇ g / tumor vehicle 10% DMSO / DW
  • a casein mixed diet was provided for 2 weeks.
  • the treatments in the four groups are as follows: Group 1: vehicle + casein mixed diet (control group) 2 groups: 5FU + casein diet diet Group 3: vehicle + BCAA dietary food four groups: 5FU + BCAA dietary diet tumor volume from a tumor outside using calipers (long diameter x short diameter x height (mm 3)) to measure the To monitor changes in tumor volume over time. Necropsy was performed on day 43 and tumor weight and volume were measured.
  • Example 5 Effect of BCAA on expression of stem cell marker in human colon cancer cell line HCT116 HCT116 cells (human colon cancer cell line) were seeded on a plate at 4000 cells / well and in 2 mM BCAA or LC 2.5% medium. Cultured for 72 hours. After culturing for 72 hours, the cells were collected, incubated with an anti-CD44 antibody (primary antibody) for 1 hour at room temperature, and further incubated with a secondary antibody conjugated with Cy5 for 1 hour at room temperature. The cells were fixed with 4% paraformaldehyde, stained with Hoechst 33258 solution (incubation at room temperature for 5 minutes), the staining solution was replaced with PBS, and the ratio of CD44 positive cells was analyzed by Array Scan. CD44 is a colon cancer stem cell marker.
  • HCT116 HCT116 cells human colon cancer cell line
  • BCAA significantly reduced the expression of CD44, a marker for colon cancer stem cells, in HCT116 cells. From the above results, it was suggested that BCAA induces not only liver cancer stem cells but also colon cancer stem cells to non-stem cells.
  • HCT116 human colon cancer cell line
  • Example 7 Effect of BCAA on metastasis of human colon cancer cell line HCT116 (in vivo test) 1 ⁇ 10 5 human colon cancer cells HCT116 were transplanted into BALB / c nude mice (female, 6 weeks old, 5 mice in each group). HCT116 cells were previously treated with 4 mM BCAA for 7 days. In the control group, HCT116 cells were not treated with 4 mM BCAA.
  • HCT116 cells were not treated with 4 mM BCAA.
  • the spleen After incising the muscle layer of the mouse, the spleen is exposed, the blood vessels at both ends of the spleen are loosely tied with thread, the HCT116 cells are slowly transferred to the spleen with an injection needle (100 ⁇ l), and the threads at both ends are tied to stop hemostasis. Thereafter, the spleen was removed, the muscle layer was sutured, and the skin was stapled. After normal breeding of the mice for 3 weeks, the mice were euthanized and the
  • Example 8 Effect of combined use of 5FU and BCAA on human gastric cancer cell line MKN45 (in vitro test) MKN45 cells (human gastric cancer cell line) were seeded in a 96-well plate at 4000 cells / 100 ⁇ l / well and cultured for 72 hours under the following conditions: LC medium (10% FBS) LC medium + BCAA (2 mM or 4 mM) LC medium + 5FU (0.05 ⁇ g / ml, 0.1 ⁇ g / ml, 0.5 ⁇ g / ml or 1 ⁇ g / ml) LC medium + BCAA (2 mM or 4 mM) + 5FU (0.05 ⁇ g / ml, 0.1 ⁇ g / ml, 0.5 ⁇ g / ml or 1 ⁇ g / ml)
  • WST-8 reagent was added (10 ⁇ l / well), and after 1 hour of color development, the absorbance at OD 450 nm was measured.
  • the absorbance of each group was expressed as a relative value when the absorbance of the unstimulated group was 100%.
  • WST-8 is reduced by intracellular dehydrogenase to produce water-soluble formazan, and the number of viable cells can be easily measured by directly measuring the absorbance of this formazan at 450 nm. The number of cells and the amount of formazan produced are in a linear proportional relationship.
  • Example 9 Effect of combined use of 5FU and BCAA on human gastric cancer cell line MKN45 (in vitro test) MKN45 cells (human gastric cancer cell line) were seeded in a 96-well plate at 4000 cells / 100 ⁇ l / well and cultured for 72 hours under the following conditions: LC medium (10% FBS) LC medium + BCAA (2 mM or 4 mM) LC medium + 5FU (0.05 ⁇ g / ml or 0.1 ⁇ g / ml) LC medium + BCAA (2 mM or 4 mM) + 5FU (0.05 ⁇ g / ml or 0.1 ⁇ g / ml)
  • Example 10 Effect of BCAA on expression of stem cell marker in human gastric cancer cell line MKN45 MKN45 cells (human gastric cancer cell line) were seeded in a 96-well plate at 4000 cells / 100 ⁇ l / well and RPMI 1640 medium (10% FBS) or BCAA The cells were cultured in RPMI 1640 medium (2% or 4 mM) (10% FBS) for 72 hours. After 72 hours, the supernatant was removed, fixed with paraformaldehyde, incubated with an anti-CD44 antibody (primary antibody) for 1 hour at room temperature, and further incubated with a secondary antibody conjugated with Texas Red for 1 hour. The supernatant was removed, and after nuclear staining with Hoechst reagent, the ratio of CD44 positive cells was analyzed in the target activation mode of Array Scan.
  • RPMI 1640 medium 2% or 4 mM
  • BCAA significantly reduced the expression of CD44, a marker for gastric cancer stem cells, in MKN45 cells. From the above results, it was suggested that BCAA induces differentiation of gastric cancer stem cells into non-stem cells.
  • Example 11 Effect of combined use of TS-1 and BCAA on human gastric cancer cell line MKN45 (in vivo test)
  • Six weeks old female BALB / c nude mice were transplanted subcutaneously with 1 ⁇ 10 6 MKN45 cells / mouse.
  • grouping was performed based on tumor volume.
  • TS-1 10 mg / kg (vehicle 0.5% CMC)
  • TS-1 10 mg / kg + BCAA 0.75 g / kg or BCAA 0.75 g / kg was orally administered every day except Saturdays and Sundays for 6 weeks. That is, the treatments in the four groups are as follows: Group 1: CMC (vehicle) Group 2: TS-1 Group 3: TS-1 + BCAA Group 4: BCAA
  • TS-1 is an anticancer agent containing tegafur, gimeracil, and oteracil potassium in the following composition.
  • Tegafur 20mg in TS-1 0.2g Gimeracil 5.8mg
  • Oteracil potassium 19.6mg
  • tumor volume major axis x minor axis x height (mm 3 )
  • Necropsy was performed on day 43 and tumor weight and volume were measured.
  • Example 12 suspending the effects MDA-MB231 cells of 5FU and BCAA against proliferation and stem cell marker expression of human breast cancer cell line MDA-MB231 in RPMI-10% (RPMI medium containing 10% FBS), 2000 cells / well Sowing on plates. The next day, the medium was changed as follows and cultured for another 5 days.
  • Group 1 RPMI-10%
  • Group 2 RPMI-10% containing BCAA (4 mM)
  • Group 3 RPMI-10% containing 5-FU (0.25 ⁇ g / ml)
  • Group 4 RPMI-10% containing 5-FU (0.25 ⁇ g / ml)
  • the results are shown in FIGS.
  • the number of viable cells was reduced by treatment with 5FU alone, and when BCAA was used in combination, the decrease in the number of viable cells by 5FU was enhanced. From the above results, it was suggested that BCAA enhances the anti-tumor effect of 5FU in breast cancer. In addition, BCAA tended to decrease the expression of CD44, a marker for breast cancer stem cells, in MDA-MB231 cells. From the above results, it was suggested that BCAA may induce differentiation of breast cancer stem cells into non-stem cells.
  • Example 13 Effect of BCAA on stem cell marker expression of human liver cancer cell line HAK1B (in vivo test) Seven-week-old female BALB / c nude mice (purchased from Nippon Charles River) were subcutaneously transplanted with 7 million HAK1B cells / individual. One week later, grouping was performed based on the tumor area. 5FU 250 ⁇ g / tumor (vehicle 10% DMSO / DW) was administered intratumorally (see Cancer Research, 70 (11), 4687-4697, 2010) and 3 (w / w)% BCAA diet or 3 (w / W) A casein mixed diet was provided for 2 weeks. That is, the treatments in the four groups are as follows: Group 1: vehicle + casein mixed diet (control group) 2 groups: 5FU + casein mixed diet 3 groups: vehicle + BCAA mixed diet 4 groups: 5FU + BCAA mixed diet
  • the primers used for RT-PCR are the same as in Example 1.
  • BCAA decreased EpCAM, a marker of liver cancer stem cells in HAK1B cells.
  • EpCAM a marker of liver cancer stem cells in HAK1B cells.
  • Example 14 Effect of combined use of BCAA on stem cell marker expression of human gastric cancer cell line MKN45 (in vivo test)
  • Six weeks old female BALB / c nude mice were transplanted subcutaneously with 1 ⁇ 10 6 MKN45 cells / mouse.
  • grouping was performed based on tumor volume.
  • TS-1 10 mg / kg (vehicle 0.5% CMC)
  • TS-1 10 mg / kg + BCAA 0.75 g / kg or BCAA 0.75 g / kg was orally administered every day except Saturdays and Sundays for 6 weeks. That is, the treatments in the four groups are as follows: Group 1: CMC (vehicle) Group 2: TS-1 Group 3: TS-1 + BCAA Group 4: BCAA
  • the primers used for RT-PCR are as follows.
  • BCAA reduced the expression of CD44, nanog and ABCB5 in MKN45 cells.
  • the above results suggest that BCAA increases the sensitivity of tumors to TS-1 by inducing differentiation of cancer stem cells of gastric cancer into cancer non-stem cells and reducing the number of cancer stem cells even in vivo. It was.
  • Branched-chain amino acids promote the differentiation of cancer stem cells into cancer non-stem cells and increase sensitivity to chemotherapeutic agents, so they are combined with chemotherapeutic agents and administered to patients with cancers that contain cancer stem cells By doing so, it is possible to treat cancer effectively.
  • metastasis and recurrence of cancer can be effectively prevented by administering a branched chain amino acid in combination with a chemotherapeutic agent to a patient with a history of cancer including cancer stem cells. Therefore, the present invention is useful as a medicine for preventing or treating cancer.

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Abstract

La présente invention concerne un agent pour potentialiser l'activité antitumorale d'un agent chimiothérapique ciblant le cancer qui contient des cellules souches cancéreuses, comprenant au moins un acide aminé à chaîne ramifiée choisi parmi l'isoleucine, la leucine et la valine ou un de leurs sels. L'invention concerne également un agent pour traiter le cancer qui contient des cellules souches cancéreuses, comprenant au moins un acide aminé à chaîne ramifiée choisi parmi l'isoleucine, la leucine et la valine ou un de leurs sels, et un agent chimiothérapique combiné. L'invention concerne également un agent pour prévenir les métastases ou la récidive du cancer qui contient des cellules souches cancéreuses, comprenant au moins un acide aminé à chaîne ramifiée choisi parmi l'isoleucine, la leucine et la valine ou un de leurs sels, et un agent chimiothérapique combiné.
PCT/JP2012/053757 2011-02-17 2012-02-17 Potentialisateur de l'activité antitumorale d'un agent chimiothérapique WO2012111790A1 (fr)

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JP2012558030A JP6090836B2 (ja) 2011-02-17 2012-02-17 化学療法剤の抗腫瘍活性増強剤
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WO2014188994A1 (fr) * 2013-05-20 2014-11-27 公立大学法人横浜市立大学 Procédé d'amplification de cellules utilisant une préparation d'acides aminés

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WO2016181335A1 (fr) 2015-05-14 2016-11-17 Professional Dietetics S.P.A. Compositions comprenant des acides aminés pour une utilisation dans le traitement de mucosites chez le patient atteint de néoplasie traité par radiothérapie et/ou chimiothérapie
CN104814375B (zh) * 2015-05-22 2018-05-15 浙江海力生生物科技股份有限公司 一种肿瘤患者全营养配方食品及其制备方法
IT201700087359A1 (it) 2017-07-28 2019-01-28 Professional Dietetics Spa Composizioni comprendenti amino acidi per l'uso nel trattamento di malattie associate a disfunzione mitocondriale
CN110786518B (zh) * 2018-08-01 2023-08-18 复旦大学附属肿瘤医院 一种用于预防、延缓胰腺癌及癌前病变的代餐组合物及其应用
IT202000000454A1 (it) * 2020-01-13 2021-07-13 Professional Dietetics Spa Composizioni comprendenti amino acidi per la prevenzione e il trattamento del cancro
IT202000000442A1 (it) * 2020-01-13 2021-07-13 Professional Dietetics Spa Composizioni comprendenti amino acidi per l'uso nella prevenzione e nel trattamento di effetti collaterali della chemioterapia
CN114983992A (zh) * 2022-06-07 2022-09-02 天津医科大学朱宪彝纪念医院(天津医科大学代谢病医院、天津代谢病防治中心) 高支链氨基酸在制备用于抑制乳腺癌肿瘤生长和肺转移方面的应用

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JPWO2014188994A1 (ja) * 2013-05-20 2017-02-23 公立大学法人横浜市立大学 アミノ酸製剤による細胞増幅法

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